This invention relates to a composition and a method for treating herpes simplex infections in humans. More particularly, this invention relates to a pharmaceutical composition containing inferferon and an antiviral surface active agent, and to a method for treating herpes simplex infections in humans by topically administering said pharmeceutical composition to the affected area.
Infections by herpes simplex virus are extremely common in humans. The virus is transmitted by direct contact with infected individuals and it is estimated that more than half the human population has been infected by herpes simplex virus at one time or another.
Once an individual is infected, the virus manifests itself as sores or lesions on various parts of the body. Herpes labialis is the most common clinical form of herpes simplex virus infection. The symptoms include inflammation of the mouth and gums as well as mouth eruptions (cold sores). The cold sores are often painful and unsightly.
In another common clinical form, herpes genitalis, eruptions occur in the genital area. Herpes gentialis is a serious problem. It often causes severe psychological and social problems in affected individuals. It can be fatal to patients with deficient immune systems. In addition, it presents the risk of infections to the newborns of infected mothers, often a fatal disease to the infant.
Herpes simplex virus may also infect the eye producing acute keratitis, and may infect the central nervous system resulting in a severe encephalitis.
Although it was once thought that there was only one type of herpes simplex virus, it is now known that there are two major types of the virus. Herpes simplex virus type 1 (hereinafter HSV-1) is usually associated with herpes labialis. Herpes simplex virus type 2 (hereinafter HSV-2) is usually associated with herpes genitalis. However, HSV-1 has been isolated in some instances from genital lesions, while HSV-2 has been isolated from lesions on parts of the body other than the genitalis. In some reports, HSV-1 has been linked to lip cancer while HSV-2 has been linked to cervical and vulvar cancer.
Following the initial infection with either HSV-1 or HSV-2 lesions may or may not appear. However, the virus does not die but continues to reside in a latent form in the nerve ganglia. Recurrent attacks may occur throughout life in response to non-specific stimuli, for example, in response to changes in body temperature, stress, ultraviolet radiation, hormonal changes, etc. It is believed by some that recurrent attacks occur when the host's immune system is suppressed. At that time, virus latent in the ganglia travels along the nerve cells without damaging them until it emerges from the ends of the nerves. As it emerges, the virus infects the adjacent cells and begins to multiply.
Viral multiplication takes place in two stages eventually resulting in a lesion. In the first stage, known as the prodromal stage, the number of viral particles increases until a first maximum is reached. During this stage, the patient may feel a tingling sensation at the site of viral multiplication. The number of viral particles decreases thereafter. About two to three days after the prodromal stage, the viral particles undergo a second stage of multiplication. In the second stage, the number of viral particles increases until a second maximum, much larger than the first maximum, is reached. The second stage of multiplication causes the death of many cells and results in a lesion. Usually, the lesion heals within 10 to 14 days but in some cases the lesion can last much longer.
Many claims have been made for effective antiherpetic compositions. Undoubtedly, the benefits demonstrated by many of these compositions in in vivo tests may be attributed to a placebo effect. This effect may be as high as 50% for herpes simplex viral infections. One group of chemical agents which proved effective against herpes simplex virus in in vitro tests is the group comprising lipid-dissolving anionic and cationic surface active agents. The effectiveness of these agents has been attributed to their ability to dissolve the lipid-containing membrane which surrounds the nucleocapsid of both HSV-1 and HSV-2.
More recently, it has been discovered by one of the inventors herein along with others that nonionic surface active agents are also effective in reducing the infectivity of herpes simplex virus. For example, in Asculai, S.S., et al., Antimicrobial Agents and Chemotherapy, 13, 686 (1978), it is reported that certain nonionic surface active agents rapidly reduced the infectivity of HSV-1 and HSV-2 in vitro. The nonionic surface active agents which inactivated the infectivity of herpes simplex virus were those possessing ether or amide linkages between the hydrophilic and the hydrophobic portions of the molecule. See also U.S. Pat. Nos. 4,020,183 (Asculai, et al.) and 4,139,630 (Asculai, et al.). The therapeutic effect of these nonionic surfactants was also attributed to their ability to dissolve the lipid-containing envelope of herpes simplex virus. The nonionic surfactants were also reported to destroy partially the nucleocapsid of the virus. The nonionic surfactants find use as spermicides in vaginal contraceptives. Contraceptive formulations containing nonionic surfactants were also demonstrated to be effective against herpes simplex virus.
The treatment of herpes simplex virus infections by topical administration of surface active agents, whether anionic, cationic, or nonionic, does not produce entirely satisfactory results. The most beneficial results are obtained when the surfactant is applied during the prodromal stage before the lesion appears. However, it is often difficult to tell when the virus is in the prodromal stage of multiplication. Furthermore, the surface active agent is applied to the uppermost layer of infected cells. Because of the dilution effect, the cells below the uppermost layer do not receive sufficient amounts of the surface active agent to destroy the viral particles. Thus, no protection is provided for cells below the surface layer and herpes simplex virus continues to multiply in those cells below the surface layer. Additionally, treatment with the antiviral surface active agent does not appear to reduce the frequency of recurrent attacks. It is believed however, that recurrent attacks might be prevented if sufficient numbers of the multiplying viral particles are destroyed.
It would thus be desirable to provide a pharmaceutical composition which reduces the load of herpes simplex virus so that latency is not reestablished.
It would also be desirable to provide a pharmaceutical composition which prevents spread of the virus to cells below the surface layer.
Human interferon is known to protect cells against viral infections. Human interferon is produced by cells in reaction to the presence of specific inducers, such as viruses. It may be produced in vivo by the cells of living organisms, or it may be produced in vitro by cell cultures in response to the presence of the inducer. There are now known to be three main varieties of human interferon: leukocyte or .alpha., fibroblast or .beta., and immune or .gamma. interferon. There are also known to be several sub-varieties of human leukocyte and fibroblast interferon.
Human interferon is relatively nontoxic and nonantigenic in humans. It is also extremely effective against a broad spectrum of viruses, including herpes simplex virus, even at very low concentrations. Until the present, treatment of herpetic lesions with human interferon has proceeded along two main courses: (a) medicinal induction of endogenic interferon in the patient, and (b) administration of exogenic interferon to the patient.
For example, U.S. Pat. No. 4,053,582 (Stickl) discloses a method for treating herpes simplex infections in humans by administering attenuated fowl pox virus to the patient. The attenuated virus induces the patient to produce his own interferon. The herpetic lesions heal within a short time after induction.
U.S. Pat. Nos. 4,061,538 (Dorner et al.) and 4,184,917 (Dorner et al.) disclose a method of treating herpes simplex viral infections by administering structurally modified interferons to the patient. In these patients, the modified interferons are administered systemically to the patient.
Several published reports also disclose the treatment of herpetic eye infections by topical administration of human interferon. For example, see D. Naumann-Haefelin, et al., in Infection and Immunity, 17, 468 (1977) and B. R. Jones, et al., in Lancet ii, 128 (1976).
None of these disclosures suggests the treatment of herpes labialis and herpes genitalis in humans by administering topically an interferon-containing pharmaceutical composition. Moreover, none of these disclosures suggests the treatment of herpes simplex viral infections by administering topically a combination of human interferon and an antiviral surface active agent.
Accordingly, it is an object of the present invention to provide novel pharmaceutical compositions containing human interferon and an antiviral surface active agent.
It is also an object of the present invention to provide a method for treating lesions due to herpes simplex virus by topically administering the aforesaid pharmaceutical compositions.
It is further an object of the present invention to provide compositions for treating herpetic lesions which not only heal the lesions but may also reduce recurrent attacks.
How these and other objects of this invention are achieved will become apparent in light of the accompanying disclosure and claims.